Dan Cole, Geoff Parling and Manu Tuilagi retain their starting places from the final fixture of the Six Nations against Ireland.
Ben Youngs returns at scrum-half in place of Lee Dickson (Northampton Saints), who moves to the bench. Tigers fly-half Toby Flood, the most experienced member of the squad with 47 caps, is named on the bench.
Head coach Stuart Lancaster gives debuts to Exeter Chiefs flanker Tom Johnson and Harlequins prop Joe Marler.
In the back three Northampton’s Ben Foden moves to the left wing for David Strettle and to accommodate Harlequins’ Mike Brown at full back.
England Head Coach Stuart Lancaster said: “It is competitive in lots of positions but particularly at scrum half. We are really pleased with Ben's form and he knows our systems well. Lee, if he gets his chance from the bench I am sure will make an impact.
“We have made no secret of how tough this series will be but it is an opportunity we do not fear and with the 22 we have selected, including an experienced bench, I am confident that we can perform.”
Elsewhere, Owen Farrell starts at fly-half and Scarlets No.8 Ben Morgan retains his place. London Irish centre Jonathan Joseph, 21, could also make his Test debut as a replacement.
England (v South Africa, Mr Price Kings Park, 1600 BST, live on Sky Sports HD)
15 Mike Brown (Harlequins)
14 Chris Ashton (Northampton Saints)
13 Manusamoa Tuilagi (Leicester Tigers)
12 Brad Barritt (Saracens)
11 Ben Foden (Northampton Saints)
10 Owen Farrell (Saracens)
9 Ben Youngs (Leicester Tigers)
1 Joe Marler (Harlequins)
2 Dylan Hartley (Northampton Saints)
3 Dan Cole (Leicester Tigers)
4 Mouritz Botha (Saracens)
5 Geoff Parling (Leicester Tigers)
6 Tom Johnson (Exeter Chiefs)
7 Chris Robshaw (capt, Harlequins)
8 Ben Morgan (Scarlets)
16 Lee Mears (Bath Rugby)
17 Paul Doran Jones (Northampton Saints)
18 Tom Palmer (Stade Francais)
19 Phil Dowson (Northampton Saints)
20 Lee Dickson (Northampton Saints)
21 Toby Flood (Leicester Tigers)
22 Jonathan Joseph (London Irish)
South Africa head coach Heyneke Meyer, the former Tigers head coach, has named his team for the game and gives debuts to locks Juandre Kruger and Eben Etzebeth and flanker Marcell Coetzee. A fourth newcomer, prop Coenie Oosthuizen, could make his first appearance off the bench.
South Africa: 15 Zane Kirchner, 14 JP Pietersen, 13 Jean de Villiers, 12 Frans Steyn, 11 Bryan Habana, 10 Morné Steyn, 9 François Hougaard, 8 Pierre Spies, 7 Willem Alberts, 6 Marcell Coetzee, 5 Juandré Kruger, 4 Eben Etzebeth, 3 Jannie du Plessis, 2 Bismarck du Plessis, 1 Tendai Mtawarira
Replacements:16 Adriaan Strauss, 17 Coenie Oosthuizen, 18 Flip van der Merwe, 19 Keegan Daniel, 20 Ruan Pienaar, 21 Patrick Lambie 22 Wynand Olivier